Description: (Applicant's Description) The goals of the Immunology Program are directed towards defining new pathways for immune activation against tumor cells for the purpose of translation to the clinic. To develop an outstanding program, effort has been put into (1) recruiting and retaining outstanding faculty focused on tumor immunology and therapy, (2) creating a physical and mental environment that readily brings members within and outside of the Program together for spontaneous interactions and scientific collaborations, (3) promoting activities tied to gene and immunotherapy of cancer as a bridge to the Clinical Investigations Program. Program members have concentrated on translational research based on molecular immunology and developmental immunotherapy. In addition to analyzing the signals that are required for immune cells to be optimally activated past tolerance, signal events involved in lytic function against tumor cells and prevention of apoptosis are addressed. Other areas of research include lymphocyte and stem cell development, and analysis of mechanisms for up- or down- regulation of the immune system. In order for successful immune recognition, tumor cell antigens must be presented appropriately in the context of major histocompatibility complex Class I and II. Thus, another emphasis is on MHC Class I and II-related gene regulation and antigen processing. Molecules identified to be critical for immune activation are then tested in animal models, using gene therapy approaches. The Specific Aims are: (1) to understand how tumor antigens are expressed and processed, (2) to define cellular and molecular mechanisms for lymphocyte and myeloid cell development and function, and (3) to develop novel immunotherapeutics for cancer. The Immunology Program has 14 members, with the current funding base of 18 NIH grants (eight from NCI), one NCI training grant, one ACS grant, two VA grants and one AHA grant, totaling approximately $2.6 million in annual direct cost. In comparison to 1997, when 12 members carried eight NIH grants (three from NCI), two NIH training grants and five other grants for a total of $1.6 million, the Immunology Program has more than doubled its funding from NIH/NCI and markedly increased its overall funding level.